Process for preparation of 3-substituted amino-delta1, 3, 5(10)-estratrienes and 19-nor-delta 1, 3, 5(10)-pregnatrienes



United States Patent "ice PROCESS FOR PREPARATION OF 3-SUBSTHTUTED AMINO-A -ESTRATRIENES AND 19-N6R- A -PREGNATRIENES Francisco Alvarez, Palo Alto, Calif., assigior to Syutex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Mar. 11, 1965, Ser. No. 439,084

18 Claims. (Cl. 260-2395) This invention relates to a novel process for the preparation of cyclopentanopolyhydrophenanthrene derivatives and to novel cyclopentanopolyhydrophenanthrene derivatives prepared thereby.

More particularly, this invention relates to a novel process for the preparation of 3-substituted amino- A -estratrienes and 3-substituted amino-19-nor- A -pregnatrienes, which process can be illustrated schematically as follows, using, for the sake of simplicity,

only the A and B rings of the steriod nucleus:

In these formulas R represents a keto group or a ketalized keto group, i.e., a cycle (lower) alkylenedioxy group such as cycloethylenedioxy, cyclopropylenedioxy, or the like, R represents hydrogen or an acyl group, the symbol 5 indicates that the hydroxyl or acyloxy group attached to the carbon atom at the 6-position of the steroid nucleus can be in either the aor the B-configuration, and R and R represent hydrogen, a hydrocarbon radical, e.g., an alkyl (including straightand branched-chain alkyl and cycloalkyl), alkenyl (including straightand branched-chain alkenyl and cycloalkenyl) or aryl (including alkaryl and aralkyl) group, preferably one containing rom 1 to 19 carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, vinyl, allyl, methallyl, cyclohexanyl, phenyl, tolyl, Xlyl or benzyl, or, taken singly or together, a saturated or unsaturated (including aromatic) fused hydrocarbon ring structure, preferably one containing from 9 to 30 carbon atoms, inclusive, such as indanyl, indenyl, naphthyl, acenaphthenyl, anthnyl or cyclopentanopolyhydrophenanthryl rings, or, taken singly or together, a heterocyclic ring system such as pyrryl, pyrrolidyl, pyridyl, piperridyl, furyl, furfuryl, morpholinyl or thienyl, all of which can either be unsubstituted or can contain or be substituted with one or more non-interfering substituents, e.g., hydroxyl groups, acyloxy groups, esterified carboxy groups, ether groups, such as methoxy and tetrahydropyranyl-oxy groups, ketal groups, such as cycloethylenedioxy and cyclopropylenedioxy groups, amino (including substituted amino) groups, nitro groups, halogen atoms, such as fluorine, chlorine and bromine, and the like, with at least one of R and R being other than hydrogen.

The acyloxy and acyl groups referred to herein are preferably derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclicaliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, :alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. T ypioal ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, tbutylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and B-chloropropionate.

In addition to the substituents shown at the 3- and 6- 3,293,244 Patented Dec. 20, 1966 positions of the steriod nucleus in partial Formula A hereinabove, the conventional substituents found at the l7-position in androstane derivatives, Le, :a -hydroxy or acyloxy group together with a Net-hydrogen atom, lower alkyl group, lower alkenyl group or lower alkynyl group, or a 17-keto group or ketalized keto group, and those found in the 17-, 20-, 21- and the 16-position in pregnane derivatives, e.g., a 17,6-acetyl side chain, with or Without a 17a-hydroXy or acyloxy substituent, a 17 8- acetyl side chain having a ketalized 20-keto group, a dihydroxyacetone side chain wherein the hydroxyl groups are either free or functionally converted, e.g., one wherein one or both of the hydroxyl groups have been esterified or wherein the entire side chain has been converted to a bisrnethylenedioxy grouping, a 1611- or 16,3-hydroxy, acyloxy or methyl group, a 16a,17B-cyclic acetal or ketal grouping, such as a 16a,l7a-isopropylidenedioxy grouping or the like, the steriod starting materials employed in the novel process of the present invention can also contain other non-interfering substituents. Included among such substituents are keto groups or derivatives thereof, such as enol ether or ketal groups, hydroxyl groups or derivatives thereof, such as ether, ester, acetals or ketal derivatives, alkyl groups, such as methyl, ethyl or propyl groups, nitro groups, amino (including substituted amino) groups, halogen atoms, such as fluorine, chlorine or bromine, and the like, which, depending on the particular substituent and steriod in question, can be present at one or more positions 1, 2, 4, 7, 8, 9, ll, 12, 13, 14, 15, 16, 18, 19, 20 or 21 on the steriod nucleus.

The A -6-hydroxy-3-keto steriods and 6-acylates and 3-ketals thereof employed as starting materials in the novel process of the present invention can themselves be prepared as described in my copending US. patent application Serial No. 382,361, filed July 13, 1964. Included among these compounds are: A -estren-6a-ol-3,17-dione, A -estren-6a-ol-3,17-dione 6-acetate, A -estren-6B-o1-3, 17-dione, A -estren-6/8-ol-3,17-dione 6-acetate, A -estren-6ix,17,3-diol-3-one, A -estren-6a,l7fi-diol-3-one 6,17-diacetate, A -estrene-6/3,17/3-diol-3-one, A -estrene-6 B,17fl-diol-3-one 6,17-diacetate, 17a-me11hyl-A -estren-6a,17i3-diol-3-one, l7a-methy1-A -estrene-6a,17fl-diol-3-one 6-acetate, l7u-methyl-A -estrene--6/3,l7fi-diol-3-one, 17a-methyl-A -estrene-6fi, l 7fi-diol-3-one 6-acetate, 17ix-vinyl-A5 -estrene-6a,l7u-diol-3-one, 17a-vinyl-A -estrene-6a, l7fl-diol-3-one 6-acetate, 17a-vinyl-A -estrene-6B,17B-diol-3-one, 17ot-vinyl-A -estrene-6/3,17,6-diol-3-one G-acetate, 17a-'ethyny1-A -estrene-6 x, l7fi-dio|l-3-one, 17a-ethynyl-A -estrene-6a,l7,8diol-3-one 6-acetate, l7u-ethynyl-A -estrene-GB,17B-diol-3-one, 17a-ethynyl-A -estrene-6fl,17,8-diol-3-one 6-acetate, 19-nor-A -pregnen-6ot-ol-3,ZO-dione, 19-nor-A -pregnen-6a-ol-3,20-dione 6-acetate, 19-nor-A -pregnen-6fl-ol-3,20-dione, 19-nor-A -pregnen-6fi-ol-3,20 dione 6-acetate, 19-n0r-A -pregnene-6 ot,17a-diol-3,20-dione 17-acetate, 19-nor-A -pregnene-6a,17a-diol-3,20-dione 6,17-diacetate, 19-nor-A -pregnene-6/3,17u-diol-3,20-dione 17-acetate, 19-nor-A -pregnene-6fi,17u-diol-3,20-dione 6,17-diacetate, 19-nor-A -pregnene-6a,20e-diol-3-one, 19-nor-A -pregnene-6m,20's-diol-3-one 6,20-diacetate, 19-nor-A -pregnene-6fi,20*e-diol-3-one, l9-nor-A -pregnene-6,8,20e-diol-3-one, 6,20-diacetate, 16a,l7ot-isopropylidenedioxy-l9-nor-A -pregnen-6otol-3,20-dione 6-acetate,

3 15oz, 17a-isopropylidenedioxy-l 9-nor-A -pregnen-6 3- ol-3,20-dione G-acetate, 17,20;21,2l-bismethylenedioxy-l9-nor-h -pregnen- 6OL-O1-3,11-dl01'l8 6-acetate, l7,20;20,21-bismethylenedioxy-19-nor-A m-pregnen- 6fl-ol-3,l1-dione 6-acetate,

V 3, 17-bis cycloethylenedioxy -A -estren-6u-ol,

3,17-bis(cycloethylenedioxy) -A -estren-6 OL-Ol 6-acetate,

3,17-bis(cycloethylenedioxy) -A -estren-6,B-ol,

3,l7-bis(cycloethylenedioxy)-A -estren-6fl-ol 6-acetate,

3 -cycloethylene-dioxy-17a-methy1-A -estrene-6 a, 17 5- diol 6-acetate,

3-cycloethylenedioxy-l7u-methyl-A -estrene-6,8,l7(3- diol 6-acetate,

3-cycloethylenedioxy-17u-ethynyl-A -estrene-6a,17p

diol 6-acetate,

3-cycloethylenedioxy- 1 7a-ethynyl-A -estrene-6,B, 1718- diol G-acetate,

3,20-bis (cycloethylenedioxy) -1 9-nor-A -pre gnen-fiuol, 3,20- bis (cyrcloethylenedioxy) -19-nor-A -pregnene-6aol 6-acetate, 3,20-bis (cycloethylenedioxy) -19-nor-A -pregnen-6fio1, 3,2-0-bis (cycloethylenedioxy) -19-nor-A -pregnen-6B- ol 6-acetate, 3,20-bis cycloethylenedioxy) 1 9-nor-A -pregnene-6u,

l7rx-di0l 6,17-diacetate, and 3,20-bis(cycloethylenedioxy) -19-nor-A -pregnene-6f3,

17OL-dlO1-6,'17-3.Cetat, and the like.

The amines which can be employed in practicing the novel process of the present invention are primary and secondary monoamines and polyamines in which the amino nitrogen which is ultimately bonded to the 3-carbon atom in the steroid final product can be attached to a primary, secondary .or tertiary carbon atom, e.g., to a carbon atom or atoms contained in either or both of the substituents represented by R and R in partial Formula B hereinabove.

An illustrative but by no means exhaustive listing of such amines includes aliphatic and cycloaliphatic primary monoam-ines such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, t-

butylamine, n-amylamine, 2-amino-4-methylpentane, other amyl, hexyl, heptyl, octyl and higher primary aliphatic monoamines, cyclopentylamine, cyclohexylamine, ringalkylated cyclopentyl and cyclohexylamines, vinylamine, allylamine, cyclohexenylamine, and the like, aliphatic and cycloaliphatic secondary monoamines, such as dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, N-methyl-N-n-butylamine, N-ethyl-N-nbutylamine, N-methylcyclohexylamine, N-ethylcyclohexylamine, N-butylcyclohexylarnine, dicyclopentylamine, di-

, cyclohexylamine, ring-alkylated dicyclohexylamines, and

the like, arylamines such as benzylarnine, ring-alkylated benzylamines, fi-phenylethylamine, aniline, 0-, mand p-fiuoro, chloroand bromo-aniline, omand p-nitroaniline, o-, mand p-anisidine, o-, mand p-toluidine, o-, mand p-aminoacetophenone, tetrahydro-B-naphthylamine, 5,10-dihydroacridine, N-methylaniline, diphenylamine, dibenzylamine, N-benzyl-N-methylaniline, and the like, alkylol and alkyl alkylol primary and secondary monoamines such as ethanolamine, propanolamine, diethanolamine, methylmethanolamine, methylethanolamine, ethylmethanolamine, and the like, alkylene polyamines and polyalkylene polyamines such as ethylenediamine (N,N)-diethyl-l,2-ethylene diamine, trimethylene diamine, 1,2-diaminopropane, tetramethylene diamine, diethylene triamine, triethylene tetramine, tetraethylene pentamine, tris-(B-arninopropyl)amine, 3,3'-iminobispropylamine, and the like, arylene polyamines such as o-, mand p-phenylene diamine, N,N-dimethyl-o-phenylenediamine, N,N'-di-p-tolyl-o-phenylenediamine, N-rnethylp-phenylenediamine, N,N diethyl-p-phenylenediamine, and the like, heterocyclic amines such as pyrrolidine, pi-

4 peridene, 2-, .3- and 4-pipecoline, piperazine, furfurylamine, tetrahydrofurfurylamine, morpholine, and the like, esterified amino acids such as methyl aminoethanoate, ethyl a-amino propionate, and the like, and steroidal amines such as 7-aminocholesterol, 17,8-amino-A -androsten-3,801, and the like.

In carrying out the novel process of the present invention the steroid starting material, dissolved in an inert organic solvent, eg, an aliphatic or aromatic hydrocarbon such as pentane, hexane, heptane, benzene, toluene or xylene, a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or chlorobenzene, an ether such as a dioxane or tetrahydrofuran, or the like, as well as mixtures thereof, is reacted with about 1 mol to about 10 mols of the amine, and preferably with from about 1.1 to about 1.5 mols, per mol of the steroid.

The use of small amounts of a relatively weak acid catalyst, e.g., from about 0.001 to about 10 percent by weight based on the Weight of the steroid starting material, of a weak organic acid such as acetic, propionic, oxalic or malonic acid, or the like, is preferred. However, where the amine employed is one which is capable of forming enamines in the absence of an acid catalyst, e.g., pyrrolidine or the like, the catalyst may be omitted.

The reaction can be carried out at temperatures ranging from room temperature (about 25 C.) or below to the reflux temperature of the solvent or solvent mixture employed, and will generally take from about 1 hour to about 72 hours or longer to go to completion, depending on such factors as the reactants employed, the amount and strength of the acid catalyst, if one is used, and the temperature at which the reaction is carried out.

Included among the 3-substituted amino-A -estratrienes and 3-substituted amino-l9-nor-A -pregnatrienes which can be prepared by the novel process of the present invention are those compounds represented by the general formulas:

R4 C=O l n la R2 R2 U 33 BK I II In these formulas R and R have the same meanings as set forth hereinabove for partial Formula B, R represents a hydroxyl group or an acyloxy group, R represents hydrogen, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, R and R taken together represent a keto group, and R represents hydrogen, a hydroxyl group or an acyloxy group.

Among the compounds represented by these general formulas are:

3-methy.lamino-A -estratrienl7-one, 3-methylamino-A -estratrien-17,6-01, 3-ethylamino-17a-methyl-AL -estratrien-17,8-01,

'3-cyc1ohexylamino-17 a-'vinyl-A l -estratriem 1713-01,

3-(N-p-fiuoroanilino) -17a-ethynyl-A -estratrien- 3 -diphenylamino-A -estratrien-17-one,

3-ethanolamino-A -estratrien- 1 75-01,

3-diethanolamino-A -estratrien- 175-01 17-acetate,

3-( 2'-diethylamino) -ethy-larnino-A -estratrien- 17-one,

3- 2'-diethylamino) -ethy1amino-A -estratrien- 3- 2'-diethylamino -ethylamino-A -estratrien- 175-01 17-acetate,

3-(2-diethylamino) -ethylamino-17a-methyl-A estratrien-175-ol,

3- (2'-diethylamino -ethylamino-17nt-vinyl-A estratrien- 175-01,

3-(2'-diethylamino -ethylamin- 1 7u-ethynyl-A (10) estratrien- 1 75-01,

3-(p-amino)-phenyl-amino-A -estratnien-17-one,

3-(N-.pyrrolidinyl -A -estratrien-17-one,

3-( N-pyrrolidinyl -A -estr-atrien- 175-01,

3-(N-pyrrolidinyl) A -estratrien-175-ol 17-acetate,

3-(N-pyrrolidinyl) -17ot-methyl-A -estratrien- 3-(N-pyrrolidinyl -1 7a-v-inyl-A -estratrien- 175-01,

3-(N-pyrrolidinyl) -17ot-ethynyl-A -estratrien- 3-(N-piperidinyl) -A -estratrien-17-one,

3-(N-piperidinyl) -A -estratrien-175-ol,

3-(N-piperidinyl -A -estratrien-175-ol-17-0ne,

3- (N-piperidinyl) 1 7a-methy1-A -estratrien- 175-01,

3- (N-piperidinyl 17:z-vinyl-A -estratrien-1 75-01,

3-(N-piperidinyl) -17a-ethynyl-A -estratrien- 3-(N-piperazinyl) -A -estratrien-17-one,

3- N-piperazinyl -A -estr-atrien- 175-01,

3 -(N-morpholinyl -A -estratrien-17-one,

3- (N-morpholinyl -A -estratrien- 175-01,

3-(N-carbomethoxymethyl) -A -estratrien-17-one,

3-(N-1-carbethoxyethyl) -A -estratrien-175-ol,

3-[N-17'5-amin0-A -androsten-3 '5-01 (yl) ]-A estratrien-17-one,

3-methylamir1o-19-n0r-A -pregnatrien-ZO-one,

3-diethylamin0-19-nor-A -pregnatrien-ZO-one,

3-diethylamin-o-19-nor-A -pregnatrien-17u-ol- -one,

3-diethylarnino-19-nor-A -pregnatrien-17a-ol- 20-one 17-acetate,

3-(2'-diethylamino)-ethylamino-19-nor-A pregnatrien-ZO-one,

3-(2-diethylamino) -ethylamino-19-11or-A pregnatrien-17a-ol-20-one,

3 -(2'-diethylamino -ethylamino-19-nor-A pregnatrien-17a-ol-20-one 17-acetate,

3-(N-pyrrolid-inyl) 19-n0r-A -pregnatrien-2O-one,

3-( N-pyrroldinyl) 19-nor-A -pregnatrien- 1 704-01- 20-one,

3-(N-pyrrolidinyl) -19-nor-A -pregnatrien-17a-ol- 20-one 17-acetate,

3-(N-piperidinyl) -19-nor-A -pregnatrien-20-one,

3- N-piper-idinyl) -19-nor-A -pregnatrien- 17 04-01- 20-one,

3-(N-piperidinyl) -19-nor-A -pregnatrien-17a-ol- 20-one 17-acetate,

S-(N-morpholinyl -19-nor-A -pregnatrien-20-one,

3-(N-morpholinyl) -19-nor-A -pregnatrien-17u-ol- 20-one,

3-(N-morpholinyl -19-n0r-A -pregnatrien-17a-ol- 20-one, and the like.

The novel 3-substituted amino-A -estratriens represented by Formula I hereinabove are estrogenic agents having utility in fertility control in humans and animals.

The novel 3-substituted amino-l9-nor-A -pregnatrienes represented by Formula II hereinabove are progestational agents having oral activity, and also possess v 1754 cm." 0:0

6 anti-estro-genic, anti-androgenic and anti-gonadotrophic properties.

In order that those skilled in the art can more fully understand the present invention, the following examples are set forth. These examples are given solely for the purpose of illustrating the invention and should not be considered as expressing limitations unless so set forth in the appended olairns.

Example I A solution of 750 mg. of A -estren-6a-ol-3,17-dione -acetate in 75 ml. of benzene was admixed with 4.5 ml. of diethylamine and 0.1 ml. of acetic acid, and the resulting reaction mixture was refluxed for 6 hours. Following this reaction period the reaction mixture was concentrated under vacuum to about 29 mL, then filtered through a short column of alumina, using benzene as the eluant. The material obtained from the eluate after evaporation of the benzene was purified by further column chromatography on 36 grams of unwashed alumina, using benzene/diethyl ether as the eluant. The resulting homogeneous, less polar fractions were crystallized from methylene dichloride/hexane and then recrystallized twice from methylene dichloride/methanol, thus giving 3-diethylamino A estratrien 17 one, melting point 131.5132.5 C.; kmax. 263 m s 14,420) and 310 m (6 2,145); [011 +134; :max. 1370 and 1379 cm.- (C-N), 1525, 1563 and 1584 cmf (aromatic ring) and Arzalysis.Calcd for C H ON; C, 81.18; H, 9.60; O, 4.92; N, 4.30. Found: C, 81.36; H, 10.19; 0, 4.98; N, 3.95.

Example II A solution of 720 mg. of A -est-ren6oc-ol-3,17-dione in 70 ml. of benzene was admixed with 0.7 ml. of N,N- diethyl-1,2-ethylene diamine and 0.1 ml. of acetic acid, and the resulting reaction mixture was refluxed, using a water separator, for 1 hour. Following this reaction period the reaction mixture was concentrated under vacuum to a final volume of 20 ml., then worked up in the manner described in Example I hereinabove (with the exception that the final recrystallizations were carried out using methylene dichloride/pentane rather than methylene dichloride/ methanol), thus giving 3-(2-diethylamino)-ethy1amino-A -estratrien 17 one, melting point 98-100 C.; Amax. 248 m s 13,820) and 300 302 m (6 2,050); [0th, +12l; vmax. 1370 and 1385 cm.- (C-N), 3350 cm. (N-H), 1508, 1570 and 1615 CHIC-1 (aromatic ring) and 1738 CITI. 1 (0 0). Analysis. Calcd for C H ON C, 78.21; H, 9.85; O, 4.34; N, 7.60. Found: C, 78.49; H, 9.81; O, 4.22; N, 7.54.

Example III A solution of 250 mg. of A -estren-65-ol-3,17-dione 6-acetate in 25 ml. of anhydrous benzene was admixed with 286 mg. of pyrrolidine and refluxed for 1 minute, following which the reaction mixture was allowed to stand at room temperature for 16 hours. Following this reaction period the reaction mixture was diluted with 75 ml. of benzene, washed twice with 25 ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The resulting residue was dissolved in methylene dichloride, decolorized with charcoal, crystallized from methylene dichloride/methanol, then recrystallized three times from methylene dichloride-ethanol, thus giving 3-(N-pyrrolidinyl)-A -estratrien-17-one, melting point 192 C.; kmax. 258 m (6 18,300) and 310-312 m (6 2,820); [M +148"; vmax. 1362 cm? (C-N), 1610, 1562 and 1510 cm.- (aromatic ring) and 1739 cm.- (C O). Analysisl.-Calcd for C H ON: C, 81.69; H, 9.04; O, 4.95; N, 4.33. Found: C, 81.76; H, 9.22; O, 5.07; N, 4.38.

By repeating this procedure in every detail but one, namely using A -estrene-6a,175-diol-3-one 6-acetate and A -estrene-65,175-diol-3-0ne-6,17-diacetate, re-

spectively, as the steroid starting materials, 3-(N-pyrrolidinyl)-A -estratrien-17,8-01, melting point 178180 C.; Xmax. 256 m (6 17,800) and 312 nm (e 2,750); [a1 +78"; vmax. 1370 cm.- (CN), 1525, 1562 and 1612 (aromatic ring) and 3395 CI11. 1 (OH). Analysis. Calcd for C H ON: C, 81.18; H, 9.60; O, 4.92; N, 4.30. Found: C, 80.79; H, 9.71; O, 5.17; N, 4.25 and 3-(N- pyrrolidinyl)1A -estratrien-Ufl-ol 17-acetate, melting point 137138 C.; )rmax. 258 ma (6 16,600) and 312 ma (6 2,500); {111 +51; vmax. 1359 and 1380 cm.- (C-N), 1520, 1560 and 1630 (aromatic ring), 1245 cm. (C-O) and 1750 cm. (&). Analysis.-Calcd for C H O N: C, 78.43; H, 9.05. Found: C, 78.85; H, 9.29, respectively, were obtained.

Example IV A solution of 750 mg. of 3-(N-pyrrolidinyl)-A estratrien-17-one in 35 ml. of dioxane and 0.4 ml. of water was admixed with 440 mg. of sodium borohydride, and the resulting reaction mixture was allowed to stand at room temperature for 5 hours. Following this reaction period excess sodium borohydride was decomposed by the careful addition of acetic acid, and the reaction mixture was then diluted with a large volume of Water. The resulting precipitate was collected by filtration, washed with water until neutral and dried. Recrystallization from methanol gave 3-(N-pyrrolidinyl)ai estratrien-17,6-ol, identical to that described in Example III hereinabove.

Example V A mixture of 600 mg. of 3-(N-pyrrolidinyl)-A estrat-rien-l7{i-ol, 2.5 ml. of pyridine and 1.2 ml. of acetic anhydride was heated on a steam bath for 8 hours. Following this reaction period the reaction mixture was poured into ice water and the resulting precipitate was collected by filtration, washed with water and dried. Recrystallization from methylene dichloride/methanol gave 3-(N-pyrrolidinyl)-A -estratrien-175-01 17-acetate, identical to that prepared as described in Example III hereinabove.

Example VI A solution of 500 mg. of A -estren-65-ol-3,17-dione in 50 ml. of benzene was admixed with 1 ml. of piperidine and 0.4 ml. of acetic acid, and the resulting reaction mixture was refluxed for 2.5 hours. Following this reaction period the reaction mixture was worked up in the manner described in Example III hereinabove, thus giving 3-(N- piperidinyl) Alfifitm) estratrien 17 one, melting point l43-143.5 C.; xmax. 250-252 mp. (is 11,000) and 322 m (e 1,620); [1:] +135; vmax. 1389 and 1370 cm. (C-N), 1510, 1563 and 1613 cm. (aromatic ring) and 1724 cm? (C=O). Analysis.Calcd for C H ON: C, 81.85, H, 9.26; O, 4.74; N, 4.15. Found: C, 82.33, H, 9.36; O, 4.60; N, 4.02.

Example VII The procedure of Example I hereinabove was repeated in every detail except for the following. In one run, 19- nor A -pregnen-6a-ol-3,20-dione was used as the steroid starting material, and 0.1 ml. of propionic acid was used as the catalyst. In a second run, 19-nor-A -pregnene- 6a,l7u-dlOl3,20-dl0n 6,17-diacetate was used as the The procedure of Example III hereinabove was repeated using 0.001% by weight, based on the Weight of the steroid starting material, of acetic acid as catalyst.

8 The same product, namely 3-(N-pyrrolidinyl)-A estratrien 17-one, was obtained, and the reaction was complete in five hours.

Similarly, by repeating the procedure of Example III hereinabove using the steroid starting materials and catalysts employed in Example VII hereinabove, 3-(N-pyrrolidinyl) 19 nor A pregnatrien 20 one and 3 (N pyrrolidinyl) 19 nor A pregnatrien 17cc ol 20 one 17 acetate, respectively, were obtained.

Example IX The procedure of Example I hereinabove was repeated using:

3,17 bis (cycloethylenedioxy) A5110 estren 60; 01, 3,17 bis (cycloethylenedioxy) A 0 estren 60c ol 6 acetate, 3,17 bis (cycloethylendioxy) A500) estren- 6,8 01, 3,17 bis (cycloethylenedioxy) A500) estren- 6;? ol 6 acetate, 19 nor A500) pregnen 6d -o1- 3,20- dione, 19 nor A500) pregnen 6,8 o1 3,20 dione 6 acetate, 3,20 bis (cycloethylenedioxy) 19 nor- A5l10) pregnen 60c 01, 3,20 bis (cycloethyenedioxy)- 19 nor A500) pregnen 6 0c -ol, 6 acetate, 3,20- bis (cycloethylenedioxy) 19 nor A500) pregnene 613- 01 and 3,20 bis (cycloethylenedioxy) 19- nor A pregnen 6p ol 6 acetate, respectively, as the steroid starting materials. The first four of these gave 3-diethylamino-17-cycloethylenedioxy-A -estratriene, the next two gave 3 diethylamino 19 nor A pregnatriene 20 one, identical to that prepared as described in Example VII hereinabove, and the last four gave 3-di- 'ethylamino 19 nor 20 eycloethylenedioxy A pregnatriene.

It will be obvious to those skilled in the art that other changes and variations can be made in carrying out the present invention without departing from the spirit and scope thereof as defined in the appended claims.

I claim:

1. A process for the preparation of a 3-substituted amino A steroid which comprises reacting a member selected from the group consisting of A -6-ol- 3 one; A5410) 6 acyloxy 3 one; 3 cyclo (lower)- alkylenedioxy A500) 6 01 and 3 cyclo (lower) alkyl enedioxy A5410) 6 acyloxy steroids of the estrane and 19 nor pregnane series, dissolved in an inert organic solvent, with a member selected from the group consisting of primary and secondary monoamines and polyamines, in the presence of a weak acid catalyst.

2. A process for the preparation of a 3 methylamino- A steroid which comprises reacting a member selected from the group consisting of A 6 ol 3 one; A590) 6 'acyloxy 3 one; 3 cyclo (lower)-alkylenedioxy A500) 6 01 and 3 cyclo (lower) alkylenedioxy- A500) 6 acyloxy steroids of the estrane and 19 nor pregnane series, dissolved in an inert organic solvent, with methylamine in the presence of a weak acid catalyst.

3. A process for the preparation of a 3 diethylamino- A -steroid which comprises reacting a member selected from the group consisting of A 6 ol 3 one; A500) 6 acyloxy 3 one; 3 cyclo (lower) alkylenedioxy A 6 01 and 3 cyclo (lower)-alkylenedioxy- AEUO) 6 acyloxy steroids of the estrane and 19' nor pregnane series, dissolved in an inert organic solvent, with diethylamine in the presence of a weak acid catalyst.

4. A process for the preparation of a 3-benzylamino- 115,500) steroid which comprises reacting a member selected from the group consisting of A590) 6 ol 3 one; A500) 6 acyloxy 3 one; 3 cyclo-(l-ower) alkylenedioxy-A -6-ol and 3-cyclo (lower) alkylenedioxy-A 6 acyloxy steroids of the estrane and 19 n-or pregnane series, dissolved in an inert organic solvent, with benzylamine in the presence of a weak acid catalyst.

5. A process for the preparation of a 3-(2'-diethylamino)-ethylamino-A -steroid" which comprises reacting a member selected from the group consisting of A500) 6 ol 3 ane; A 6 acyloxy 3 one; 3-

cyclo (lower) alkylenedioxy A500) 6 01 and 3 cyclo (lower) alkylenedioxy A500) 6 acyloxy steroids of the estrane and 19 nor pregnane series, dissolved in an inert organic solvent, with (N,N)-diethyl-1,2-ethylenediamine in the presence of a weak acid catalyst.

6. A process for the preparation of a 3-(N-piperidinyl)- A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A 6 acyloxy 3 one; 3 cyclo (lower) alkylenedioxy A 6 01 and 3 cyclo (lower) alkylenedioxy- A 6 acyloxy steroids of the estrane and 19 nor pregnane series, dissolved in an inert organic solvent, with piperidine in the presence of a weak acid catalyst.

7. A process for the preparation of a 3-(N-morpholinyl)-A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloXy-3-one; 3-cyclo (lower) alkylenedioxy- A -6-ol and 3-cyclo( lower) alkenedioXy-A -6-acyloXy steriods of the estrane and l9-nor pregnane series, dissolved in an inert organic solvent, with morpholine in the presence of a weak acid catalyst.

8. A process for the preparation of a B-(N-pyrrolidinyl) A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloXy-3-one; 3-cyclo (lower) alkylenedioxy- A -6-ol and 3-cyclo (lower) alkylenedioXy-A -6- acyloxy steriods of the estrane and l9-nor pregnane series, dissolved in an inert organic solvent, with pyrrolidine.

9. A process for the preparation of 3-methylamino- A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloxy-3-one; 3-cyclo (lower) alkylenedioxy- A -6-ol and 3-cyclo (lower) alkylenedioXy-A -6- acyloxy steroids of the estrane and l9-nor pregnane series, dissolved in an inert organic solvent, with methylamine in the presence of a catalytic amount of acetic acid.

10. A process for the preparation of a 3-diethylamino- A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloxy-3-one; 3-cyclo (lower) alkylenedioxy- A -6-ol and 3-cyclo (lower) alkylenedioXy-A -6- acyloxy steriods of the estrane and l9-nor pregnane series, dissolved in an inert organic solvent, with diethylamine in the presence of a catalytic amount of acetic acid.

11. A process for the preparation of a 3-benzylamino- A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloxy-3-one; 3-cyclo (lower) alkylenedioxy- A -6-ol and 3-cyclo (lower) alkylenedioxy-A -6- acyloxy steriods of the estrane and 19-nor pregnane series,

dissolved in an inert organic solvent, with benzylamine in the presence of a catalytic amount of acetic acid.

12. A process for the preparation of 3-(2-diethylamino)-ethylamino-A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloxy-3-one; 3-cyclo (lower) alkylenedioXy-A -6-ol and 3-cyclo (lower) alkylenedioxy-A -6-acyloXy steroids of the estrane and 19-nor pregnane series, dissolved in an inert organic solvent, with (N,N)-diethyl-1,2-ethylenediamine in the presence of a catalytic amount of acetic acid.

13. A process for the preparation of a B-(N-piperidinyl)-A -steroid which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloxy-3-one; 3-cyclo (lower) alkylenedioxy- A -6-ol and 3-cyclo (lower) alkylenedioxy-A -6- acyloxy steriods of the estrane and l9-n0r pregnane series, dissolved in an inert organic solvent, with piperidine in the presence of a catalytic amount of acetic acid.

14. A process for the preparation of a 3-(N-morpholinyl)-A -ster0id which comprises reacting a member selected from the group consisting of A -6-ol-3-one; A -6-acyloXy-3-one; 3-cyc1o (lower) alkylenedioxy- A -6-0l and 3-cyclo (lower) alkylenedioXy-A -6- acyloxy steroids of the estrane and 19-nor pregnane series, dissolved in an inert organic solvent, with morpholine in the presence of a catalytic amount of acetic acid.

15. A process for the preparation of 3-diethylamino- Ammo) estratriene 17 one which comprises reacting A -estren-6-ol-3,17-dione 6-acetate, dissolved in benzene, with diethylamine in the presence of a catalytic amount of acetic acid.

16. A process for the preparation of 3-(N-pyrrolidinyl)- A -estratrien-l7-one which comprises reacting A estren-6-ol-3,17-dione 6-acetate, dissolved in benzene, with pyrrolidine.

17. A process for the preparation of 3-diethylarnino- 19-nor-A -pregnatrien-20-0ne which comprises reacting l9-nor-A -pregnen-6-ol-3,20-dione 6-acetate, dissolved in benzene, with diethylamine in the presence of a catalytic amount of acetic acid.

18. A process for the preparation of 3-(N-pyrrolidinyl)- 19-nor-A -pregnatrien-20-one which comprises reacting 19-nor-pregnen-6-ol-3,ZO-dione, dissolved in benzene, with pyrrolidine,

No references cited.

LEWIS GOTTS, Primary Examiner. HENRY A. FRENCH, Assistant Examiner. 

1. A PROCESS FOR THE PREPARATION OF A 3-SUBSTITUTED AMINO - $1,3,5(10) - STEROID WHICH COMPRISES REACTING A MEMBER SELECTED FROM THE GROUP CONSISTING OF $5(10)-6-OL3 - ONE; $5(10) -6- ACYLOXY - 3 - ONE; 3 - CYCLO (LOWER)ALKYLENEDIOXY-$5(10) -6- OL AND 3 - CYCLO (LOWER) -ALKYLENEDIOXY -$5(10) -6 - ACYLOXY STERIODS OF THE ESTRANE AND 19 - NOR PREGANE SERIES, DISSOLVED IN AN INERT ORGANIC SOLVENT, WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OF PRIMARY AND SECONDARY MONOAMINES AND POLYAMINES, IN THE PRESENCE OF A WEAK ACID CATALYST.
 6. A PROCESS FOR THE PREPARATION OF A 3-(N-PIPERIDINYL)$1,3,5(10)-STEROID WHICH COMPRISES REACTING A MEMBER SELECTED FROM THE GROUP CONSISTING OF $5(10)-6-OL-3-ONE, $5(10) - 6 - ACYLOXY - 3 - ONE; 3 -CYCLO (LOWER ALKYLENEDIOXY - $5(10) -6-OL AND 3 - CYCLO (LOWER ALKYLENEDIOXY$5(10) - 6 - ACYLOXY STERIODS OF THE ESTRANE AND 19 - NOR PREGNANE SERIES, DISSOLVED IN AN INERT ORGANIC SOLVENT, WITH PIPERIDINE IN THE PRESENCE OF A WEAK ACID CATALYST. 